ABSTRACT The most frequent neurodegenerative disease is late-onset Alzheimer's disease (AD). We have recently reported a novel subgroup of patients who have a particularly malignant form of rapidly progressive late-onset Alzheimer's disease (rpAD) with atypical clinical symptoms, a low frequency of the e4 allele of APOE gene, unique structural characteristics of beta amyloid and an amyloid proteome that is distinct from typical slowly progressive Alzheimer's disease (spAD). Based on our preliminary data, we hypothesize that the rapid rates of cognitive decline and variable spectrum of symptoms in rpAD arise from the interplay between differently structured amyloid beta and tau proteins, triggering divergent pathogenetic cascades on a distinct genetic background. Accordingly, this proposal will focus on the integrated investigation of (i) conformational structural characteristics of beta amyloid and tau proteins with novel biophysical tools, (ii) proteomic profiling of amyloid plaques, neurofibrillary tangles, astrocytes and neurons of rpAD versus spAD, and (iii) genetic determinants linked to rpAD. The ultimate goal of these studies is to advance our understanding of the molecular mechanims governing the propagation of toxic beta amyloid and tau protein aggregates in the brain and the impact of their conformations upon the AD phenotype in the context of specific risk genes. This insight is critical for efforts to characterize key factors responsible for the very rapid rate of cognitive decline in this subtype of AD and ultimately to novel therapeutic strategies to slow AD progression.